Ofirmev

"The US Food and Drug Administration (FDA) has approved diclofenac sodium injection (Dyloject, Hospira Inc), a proprietary nonsteroidal anti-inflammatory drug (NSAID) for the treatment of mild to moderate pain, and for the management of mod"...

Use caution when administering acetaminophen in patients
with the following conditions: hepatic impairment or active hepatic disease,
alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration
or blood loss), or severe renal impairment (creatinine clearance ≤ 30
mL/min) [see Use In Specific Populations].

Allergy and Hypersensitivity

There have been post-marketing reports of
hypersensitivity and anaphylaxis associated with the use of acetaminophen.
Clinical signs included swelling of the face, mouth, and throat, respiratory
distress, urticaria, rash, and pruritus. There were infrequent reports of life-threatening
anaphylaxis requiring emergent medical attention. Discontinue OFIRMEV
immediately if symptoms associated with allergy or hypersensitivity occur. Do
not use OFIRMEV in patients with acetaminophen allergy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in mice and rats have been completed by
the National Toxicology Program to evaluate the carcinogenic potential of
acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed
a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated
equivocal evidence of carcinogenic activity based on increased incidences of
mononuclear cell leukemia at 0.8 times the maximum human daily dose (MHDD) of 4
grams/day, based on a body surface area comparison. In contrast, there was no
evidence of carcinogenic activity in male rats (0.7 times) or mice (1.2-1.4
times the MHDD, based on a body surface area comparison).

Mutagenesis

Acetaminophen was not mutagenic in the bacterial reverse
mutation assay (Ames test). In contrast, acetaminophen tested positive in the
in vitro mouse lymphoma assay and the in vitro chromosomal aberration assay
using human lymphocytes. In the published literature, acetaminophen has been
reported to be clastogenic when administered a dose of 1500 mg/kg/day to the
rat model (3.6-times the MHDD, based on a body surface area comparison). In
contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8-times the
MHDD, based on a body surface area comparison), suggesting a threshold effect.

Impairment of fertility

In studies conducted by the National Toxicology Program,
fertility assessments have been completed in Swiss mice via a continuous
breeding study. There were no effects on fertility parameters in mice consuming
up to 1.7 times the MHDD of acetaminophen, based on a body surface area
comparison. Although there was no effect on sperm motility or sperm density in
the epididymis, there was a significant increase in the percentage of abnormal
sperm in mice consuming 1.7 times the MHDD (based on a body surface area
comparison) and there was a reduction in the number of mating pairs producing a
fifth litter at this dose, suggesting the potential for cumulative toxicity
with chronic administration of acetaminophen near the upper limit of daily
dosing.

Published studies in rodents report that oral
acetaminophen treatment of male animals at doses that are 1.2 times the MHDD
and greater (based on a body surface area comparison) result in decreased
testicular weights, reduced spermatogenesis, reduced fertility, and reduced
implantation sites in females given the same doses. These effects appear to
increase with the duration of treatment. The clinical significance of these
findings is not known.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no studies of intravenous acetaminophen in
pregnant women; however, epidemiological data on oral acetaminophen use in
pregnant women show no increased risk of major congenital malformations. Animal
reproduction studies have not been conducted with IV acetaminophen, and it is
not known whether OFIRMEV can cause fetal harm when administered to a pregnant
woman. OFIRMEV should be given to a pregnant woman only if clearly needed.

The results from a large population-based prospective
cohort, including data from 26,424 women with live born singletons who were
exposed to oral acetaminophen during the first trimester, indicate no increased
risk for congenital malformations, compared to a control group of unexposed
children. The rate of congenital malformations (4.3%) was similar to the rate
in the general population. A population-based, case-control study from the
National Birth Defects Prevention Study showed that 11,610 children with
prenatal exposure to acetaminophen during the first trimester had no increased
risk of major birth defects compared to 4,500 children in the control group.
Other epidemiological data showed similar results.

While animal reproduction studies have not been conducted
with intravenous acetaminophen, studies in pregnant rats that received oral
acetaminophen during organogenesis at doses up to 0.85 times the maximum human
daily dose (MHDD = 4 grams/day, based on a body surface area comparison) showed
evidence of fetotoxicity (reduced fetal weight and length) and a dose-related
increase in bone variations (reduced ossification and rudimentary rib changes).
Offspring had no evidence of external, visceral, or skeletal malformations.
When pregnant rats received oral acetaminophen throughout gestation at doses of
1.2-times the MHDD (based on a body surface area comparison), areas of necrosis
occurred in both the liver and kidney of pregnant rats and fetuses. These
effects did not occur in animals that received oral acetaminophen at doses
0.3-times the MHDD, based on a body surface area comparison.

In a continuous breeding study, pregnant mice received
0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day).
These doses are approximately 0.43, 0.87, and 1.7 times the MHDD, respectively,
based on a body surface area comparison. A dose-related reduction in body
weights of fourth and fifth litter offspring of the treated mating pair
occurred during lactation and post-weaning at all doses. Animals in the high
dose group had a reduced number of litters per mating pair, male offspring with
an increased percentage of abnormal sperm, and reduced birth weights in the
next generation pups.

Labor and Delivery

There are no adequate and well-controlled studies with
OFIRMEV during labor and delivery; therefore, it should be used in such
settings only after a careful benefit-risk assessment.

Nursing Mothers

While studies with OFIRMEV have not been conducted,
acetaminophen is secreted in human milk in small quantities after oral
administration. Based on data from more than 15 nursing mothers, the calculated
infant daily dose of acetaminophen is approximately 1 – 2% of the maternal
dose. There is one well-documented report of a rash in a breast-fed infant that
resolved when the mother stopped acetaminophen use and recurred when she
resumed acetaminophen use. Caution should be exercised when OFIRMEV is
administered to a nursing woman.

Pediatric Use

The safety and effectiveness of OFIRMEV for the treatment
of acute pain and fever in pediatric patients ages 2 years and older is
supported by evidence from adequate and well-controlled studies of OFIRMEV in
adults. Additional safety and pharmacokinetic data were collected in 355
patients across the full pediatric age strata, from premature neonates ( ≥
32 weeks post menstrual age) to adolescents. The effectiveness of OFIRMEV for
the treatment of acute pain and fever has not been studied in pediatric
patients < 2 years of age. [see DOSAGE AND ADMINISTRATION - Recommended
Dosage: Children and Pharmacokinetics].

Geriatric Use

Of the total number of subjects in clinical studies of
OFIRMEV, 15% were age 65 and over, while 5% were age 75 and over. No overall
differences in safety or effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment

Acetaminophen is contraindicated in patients with severe
hepatic impairment or severe active liver disease and should be used with
caution in patients with hepatic impairment or active liver disease [see
WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY]. A reduced total
daily dose of acetaminophen may be warranted.

Patients with Renal Impairment

In cases of severe renal impairment (creatinine clearance
≤ 30 mL/min), longer dosing intervals and a reduced total daily dose of
acetaminophen may be warranted.

Last reviewed on RxList: 11/5/2013
This monograph has been modified to include the generic and brand name in many instances.